Approximately 13,000 people develop new cases of brain tumors every year [1]. Of all central nervous system (CNS) tumors, nearly 42% are specifically diagnosed as Glioblastoma Multiforme (GBM). Conventional treatment consists of surgical resection and external beam radiation. The median survival for patients undergoing surgical resection alone is 6 months while those who undergo a more complete regimen including radiation is 9 months [2]. Thus the fact remains that even aggressive treatment with established methods of surgery, radiation, and chemotherapy leads to a median survival rate of less than one year for patients diagnosed with the condition [3].
In the case of chemotherapy, some of the apparent ineffectiveness may be explained by the unique environment of the brain. The brain is a complex and delicate organ; however, it is not entirely defenseless. The body is equipped with various mechanisms specific to the CNS designed to protect and isolate it. In attempting to treat brain tumors with chemotherapy, these very defenses can become barriers to effective treatment. The Blood Brain Barrier (BBB) results from the tight gap junctions of the brain's capillaries' endothelia. The consequence of this is to effectively reduce the permeability of the capillary walls to small ions and molecules and to almost completely block permeation of large molecules such as peptides. The only type of molecules which readily cross the barrier are small, electrically neutral and lipid soluble: qualities which does not describe most chemotherapeutic agents [2]. Furthermore, the brain capillary endothelium has a reduced number of pinocytic molecules which normally transport molecules across the cells into the brain and contain proteins which actually actively remove drug molecules before they can enter the brain. In addition to the BBB, the Blood Cerebrospinal fluid Barrier (BCB) and the Blood Tumor Barrier (BTB) also work to reduce the permeation of drugs into the brain. The BCB consists of tightly bound cells of the choroid epithelium. In addition to producing the cerebrospinal fluid (CSF), these cells are also capable of actively removing organic molecules from the CSF. The BTB results from the “leaky” vasculature often found inside tumors. This leads to a net outflow of fluid from the tumor and the resulting peritumoral edema. Such edema is results in partially or completely collapsed blood vessels in the tumor, further reducing the ability of chemotherapeutic agents in the blood to penetrate into the tumor.
Thus an overall effect of the BBB, BCB, and BTB is to limit the effectiveness of systemically administered chemotherapy. New chemotherapeutic agents such as angiogenesis inhibitors, cytokines, and others are so effectively excluded by such barriers that even when orally/intravenously administered in doses high enough to cause system toxicity, their concentrations within the brain and thus the brain tumor are too low to achieve significant tumorcidal activity.
Various strategies have arisen in order to circumvent these challenges in drug delivery. These include changing drug design to increase the drugs' permeability through the various barriers, temporarily disrupting the BBB, delivering the drug via catheters directly to the brain interstitium, delivering via convection-enhanced methods, and implanting drug releasing polymers or microchips directly at the site of the tumor. Gliadel® became the first new FDA approved therapy for patients with gliomas in 23 years. It provides an effective means of directly delivering the chemotherapeutic agent carmustine or BCNU (1,3-bis(2-chloroethyl)-1-nitroso-urea). The agent is incorporated into the polymer polifeprosan 20 or pCPP-SA (poly[bis(p-.carboxyphenoxy)propane.-co-sebacic acid]) at a 3.8% (wt/wt) concentration. FIG. 1 depicts the chemical structure of carmustine and polifeprosan, i.e., the structural formulas of polymer and drug (Prescribing info). Following tumor resection, these dime sized wafers are directly placed into the tumor cavity. Up to 8 of such dime-sized wafers are implanted into the cavity where they degrade over a period of approximately 3 weeks providing a long term sustained release of BCNU directly at the site of the tumor. FIG. 2 illustrates the wafers 31 being implanted. As shown, Gliadel Wafers are implanted in a tumor resection cavity 32 [2].
Such a method of sustained local delivery is especially appropriate because tumors resulting from recurrent GBM usually form within 2 cm of the resection site of the original tumor [1]. Thus Gliadel® was first approved for use as a treatment following resection of a GBM recurrence. It has since been shown to be effective as part of a primary response as well. In both cases the treatment was shown to raise the median survival rate significantly, as shown in FIGS. 3(A)-(B). The graphs represent the survival curves showing effect of Gliadel when used to treat tumor recurrence and when used with initial therapy [5]. The therapy adds local chemotherapy to the treatment plan without limiting radiation or any other traditional therapy.
Despite the benefit provided by Gliadel® therapy, there are limitations that remain to be overcome. Currently, patients only receive the wafers after tumor resection which requires major surgery involving an open craniotomy. Thus, even if a small tumor is detected early, the patient cannot receive local chemotherapy until the tumor has grown to a size which warrants resection. The wafers degrade over approximately 3 weeks [5]. Thus once they have dissolved, they cannot be replaced without a second open craniotomy.